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1-Hydroxybenzotriazole → N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester

HRID 1058410
Notes
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Reaction equation

HRID 1058410 reaction equation
C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([CH:20]([OH:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:40][CH3:41])([O:38][CH3:39])=[O:37])[NH2:35].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:38][CH3:39])([O:40][CH3:41])=[O:37])[NH:35][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([CH:20]([OH:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][C:11]=1[Cl:10]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 2734718Methyl 2-{[(benzyloxy)carbonyl]amino}-2-(dimethyl phosphono)acetateHCID 11084793Methyl 2-amino-2-(dimethoxyphosphoryl)acetate
HCID 22661228
2-Chloro-4-(1-hydroxy-3-(3-hydroxyphenyl)propyl)benzoic acid

Product 1

HCID 18673037N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl esterYield 61%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Diisopropylethylamine (0.61 mL, 3.5 mmol) was added to a solution of rac.-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoic acid (Example 96; 270 mg, 0.88 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (397 mg, 1.2 mmol) ), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (350 mg, 0.97 mmol) and 1-hydroxybenzotriazole (131 mg, 0.97 mmol) in N,N-dimethylformamide (7 mL). The solution was stirred at room temperature for 17 h and then it was concentrated under high vacuum to remove N,N-dimethylformamide. Ethyl acetate (25 mL) was added and the solution was washed in turn with 0.5N hydrochloric acid solution (10 mL), brine (10 mL), saturated sodium bicarbonate solution (10 mL) and brine. Each of the aqueous layers was back-washed in turn with ethyl acetate (10 mL). The combined organic layers were dried (MgSO4), filtered, evaporated and the resulting residue was chromatographed over silica gel (50-100% ethyl acetate/hexanes, then 5% methanol/ethyl acetate) to flirnish N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (260 mg, 61% yield) as a colorless oil.

Workup

  1. concentrationit was concentrated under high vacuum
  2. customto remove N,N-dimethylformamide
  3. additionEthyl acetate (25 mL) was added
  4. washthe solution was washed in turn with 0.5N hydrochloric acid solution (10 mL), brine (10 mL), saturated sodium bicarbonate solution (10 mL) and brine
  5. washEach of the aqueous layers was back-washed in turn with ethyl acetate (10 mL)
  6. dry with materialThe combined organic layers were dried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customthe resulting residue was chromatographed over silica gel (50-100% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-1563c8c87b0741cfb74af285cb1eeae0
Source dataset
uspto-grants-2003_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06515124B2

Reaction notes

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